© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
Differential uptake of myocardial perfusion radiotracers in normal, infarcted, and acutely ischemic peri-infarction myocardium
Laboratorio de Cardiolog
éa Experimental del Servicio de Cardiologéa and Servicio de Medicina Nuclear, Hospital General Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
* Corresponding author. Tel. (+34-3) 489 4031; Fax (+34-3) 274 6063; E-mail: jcinca@ar.vhebron.es
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Abstract |
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 Top Abstract 1 Introduction2 Methods3 Results4 DiscussionReferences |
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Objectives: We measured the uptake of technetium-99m tetrofosmin (99mTc) and thallium-201 (201Tl) in areas of healed transmural myocardial infarction and in regions of acute peri-infarction ischemia. Methods: Anesthetised pigs with a 1-month old transmural infarction elicited by permanent ligature of the left anterior descending (LAD) coronary artery below the first branch underwent one hour of proximal LAD occlusion followed by injection of
-tetrofosmin and 
either in the left atrium (GI, n=19) or in the jugular vein (GII, n=6). Twelve other pigs (GIII) with a similar acute peri-infarction ischemia received 
-tetrofosmin and 
into the left ventricle during cardiocirculatory arrest to rule out the effect of coronary collaterals. Radiotracer counting was determined in samples from normal, acute ischemic and necrotic regions. Results: Uptake of 
-tetrofosmin and 
was greater in the infarct scar (median % of normal tissue: 20 for 
and 8.6 for 
in GI; 22 and 15 in GII) than in acute ischemic myocardium (3.2 and 2.5 in GI; 6.4 and 3.3 in GII). Radiotracer injection in arrested hearts (GIII) depicted a similar pattern (median % of injected dose: 6.2 for 
and 10 for 
in the scar; 2.3 and 4.0 in acute ischemia; and 2.9 and 3.5 in normal tissue). The infarcted region showed connective tissue and lack of viable myocardium. Conclusions: A 1-month old infarct scar with no viable myocardial tissue can take up significant fractions of 
-tetrofosmin and 
even in the absence of coronary collateral perfusion. Data suggest that the infarct scar can extract these radiotracers from the intraventricular blood.
KEYWORDS Myocardial infarction; Radioisotopes; Myocardial viability; Pigs
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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-tetrofosmin (99mTc-tetrofosmin) and 
chloride (201Tl) are extracted by metabolically active cells and based on this property, both radiotracers are widely used to assess the extent of coronary disease or to evaluate myocardial viability in patients [1, 2]. Cellular uptake of cationic 
-tetrofosmin is, in a large proportion, driven by electrical transmembrane potential differences between plasma membrane and mitochondrial membrane [3], whereas 
enters the cell through a Na+/K+ ATPase dependent process [4, 5].
Myocardial regions with a scintigraphic activity lower than 50% of normal sites are currently considered as areas of nonviable tissue [6–8], but no systematic evaluation of differential perfusion tracer uptake in coexisting ischemic and infarcted myocardial tissues has been performed. Regions of healed myocardial infarction may, theoretically, uptake 
and 
-tetrofosmin because the infarcted region contains fibroblasts, endothelial cells and an enlarged extracellular matrix mainly composed of collagen [9–11]. It is known that fibroblasts and endothelial cells are able to take up 
and 
-sestamibi in isolated cell preparations [12, 13]and on the other hand, these cationic compounds could be retained into the extracellular matrix provided that this structure contains electrically negative charged proteoglycans (glucosaminoglycans linked to proteins) that attract cations [10, 11]. The differentiation of ischemia and necrotic tissue is sometimes difficult because the ischemic myocardium may occasionally demonstrate a low perfusion disproportionate to the severity of ischemia.
Therefore this study aimed to assess the uptake of 
-tetrofosmin and 
in transmural healed myocardial infarction and in areas of contiguous acute myocardial ischemia.
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2 Methods |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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2.1 Experimental preparation
Forty-two pigs (25–30 kg) underwent a sterile left lateral thoracotomy at the fifth intercostal space under general anesthesia with sodium thiopental (30 mg/kg, IV). The fifth rib was removed and the pericardium was incised. The left anterior descending (LAD) coronary artery was dissected and was permanently ligated below the first diagonal branch. The chest was closed by layers and pleural air was aspirated. Cardiac rhythm was monitored during the ensuing two hours to treat ischemic malignant ventricular arrhythmias by external electric DC countershock. The animals were allowed to recover and all received analgesics, antibiotics, and prophylactic lidocaine (100 mg, IM).
One month after coronary ligature 37 pigs (88%) survived and underwent a midsternotomy under anesthesia with metomidate (4 mg/kg, IV) followed by alpha-chloralose (100 mg/kg, IV). The pericardium was gently detached and the LAD was reoccluded 20 to 30 mm above the primary ligature with a Prolene 5/0 snare. Blood pressure was measured with a cannula introduced into the right femoral artery and blood gases were kept within normal limits. Epicardial direct-current electrograms were recorded in the anterior surface of the left ventricle to verify the presence of acute myocardial ischemia during coronary reocclusion [14]. The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1985). The study protocol was approved by the Committee on Ethics of our institution.
2.2 Myocardial uptake of 
-tetrofosmin and 
chloride
Uptake of 
-tetrofosmin and 
was assessed one hour after induction of acute peri-infarction ischemia in the 37 surviving pigs. Radiotracers were injected during sinus rhythm either in the left atrium (group I, n=19) or in the jugular vein (group II, n=6). In 12 other pigs (group III) the radiolabelled drugs were administered during cardiac arrest to rule out the possibility that uptake in necrotic and ischemic regions was mediated by coronary collateral circulation.
The 19 pigs of group I (left atrial injection) received 5 mCi of 
-tetrofosmin and 6 of them were also treated with 1 mCi of 
. The 6 pigs of group II (jugular injection) received 0.15 mCi/kg of 
-tetrofosmin and 0.03 mCi/kg of 
. The 12 pigs of group III (arrested hearts) received a combination of 1 mCi of 
-tetrofosmin and 0.5 mCi of 
into the left ventricular cavity immediately after induction of circulatory arrest. Cardiac arrest was produced by eliciting ventricular fibrillation with an external 9 V battery applied to the epicardium. To ensure a complete cessation of coronary and systemic circulation the great cardiac vessels were clamped. 
-tetrofosmin was prepared by reconstitution of vials of Myoview (Amersham International, Buckinghamshire, U.K.) at a radioactive concentration of approximately 100 to 150 mCi/ml. The percentage of labelling efficiency was calculated in all radiotracer doses and was found to be 97.4±1.1% according to the acetone–dichloromethane method by Owunwanne. 
was prepared from a commercially available isotonic solution.
The hearts were removed 5 min after the administration of radiotracers. Cylindrical transmural tissue samples were obtained with a 6 mm biopsy punch (Zinnanti Surgical Instruments, Chatsworth, CA 91311, USA) in normal myocardium, acute ischemic region, and infarcted scar to determine the uptake (% injected dose per gram) of the two radiotracers. The biopsy punch was used to obtain tissue samples of similar size and thus ensure that the endocardial surface exposed to intracavitary radiotracer activity was comparable in all samples. This may be specially relevant if the radiotracer had the ability to diffuse into the myocardial wall. After completion of the biopsy protocol, the hearts were cut in slices spaced 10 to 20 mm from the apex to the atrioventricular ring. Radiotracer uptake in the mitral leaflets and chordae tendineae was also analyzed. Scintigraphy of myocardial slices and of cylindrical samples was performed for a period of 12 h using an Elscint Apex SP4 gammacamera. Gamma counting was determined using a LKB Wallac Universal Gamma Counter (mod 1282) appropriately adjusted for automatic spill corrections. To avoid interference between the two tracers, the system was set to measure activity within the range of two optimal counting windows obtained from the energy spectrum plot (125 to 155 keV for 
-tetrofosmin and 85 to 110 keV for 
). To prevent Compton's effect, 
was counted 24 h later. Specific radiotracer activity in the infarcted, acute ischemic and normal myocardium was presented as the % of counts per minute per gram (cpm/g) with respect to the cpm/g measured in a sample of the injected dose. The proportional uptake in the infarcted and ischemic regions was calculated as percentage of activity with respect to normal myocardium.
2.3 Histomorphologic study of ischemic and infarcted myocardium
Immediately before the administration of radiotracers a bolus of 5 ml fluorescein (20%) was injected into the left atrium to delineate the margins of the acute ischemic region. All myocardial slices taken at the end of the study were examined under ultraviolet light and the unstained portion of each section (acute ischemic myocardium) was dissected from the stained portion (normal myocardium) and both were weighted separately. The margins of the old infarction were identified after incubation of the preparation with triphenyl tetrazolium at 37°C. The unstained white area (necrotic zone) was dissected and also weighted.
Histologic examination of the infarct scar was performed in paraffin-embedded samples stained with hematoxylin-eosin and Gomori's trichrome. The width (mm) of surviving cell layers in the necrotic scar was measured under the microscope.
2.4 Statistical analysis
As the normal probability plot of values of radiotracer activity in each region revealed departures from normality, regional differences in these variables were assessed by the Kruskal–Wallis one-way analysis of variance. Descriptive statistics for radiotracer activity are expressed as median, minimum, and maximum. Data on infarct size were expressed as mean±standard deviation. A p value <0.05 was considered significant.
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3 Results |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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3.1 Uptake of
-tetrofosminPigs with acute peri-infarction ischemia injected with
-tetrofosmin either in the left atrium (group I) or in the jugular vein (group II) showed, in both circumstances, a greater radiotracer activity in the necrotic region than in the acute ischemic area. As shown in Table 1, the median radiotracer activity in the infarct zone was about 20% of that in normal tissue in group I and 22% in group II. By contrast, median radiotracer activity in acute ischemic tissue was significantly lower (3.2% in group I and 6.4% in group II, p<0.001). The differential uptake of 
-tetrofosmin in acute ischemic and necrotic myocardium was also apparent in scintigraphic views of myocardial slices and transmural biopsies (Fig. 1). Radiotracer activity through the left ventricular wall was quite homogeneous (Table 2) as denoted by data obtained in epicardial and endocardial sections of ischemic and infarcted regions. As illustrated in Table 1 a large fraction of 
-tetrofosmin was detected in samples of mitral valve leaflets (27% in group I and 23% in group II) and chordae tendineae (31% and 24%, respectively).
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-tetrofosmin and 
chloride injected into the left atrium (group I) or into the jugular vein (group II) in open chest pigs with a 1-month old anterior wall myocardial infarction submitted to 1 h of acute reocclusion of the proximal left anterior descending coronary artery
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-tetrofosmin in a 5-mm thick transversal slice of the left (L) ventricle (part A) and in transmural cylindrical samples (part B) of a pig with a 1-month old anterior infarction submitted to a second and proximal occlusion of the left anterior descending coronary artery. Diagrams show outlines of the normal myocardium (white), acute ischemia (mottled), and infarct scar (dark) together with corresponding local electrograms. The infarct scar showed greater scintigraphic activity than the acute ischemic regions.
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-tetrofosmin in transmural left ventricular samples from pig hearts with a 1-month old anterior wall myocardial infarction submitted to 1 h of acute reocclusion of the proximal left anterior descending coronary arteryInjection of
-tetrofosmin into the left ventricular cavity in arrested hearts with blocked coronary circulation (Table 2) continued to induce greater radiotracer uptake in the necrotic tissue than in areas of acute ischemic myocardium (6.2% vs. 2.3%, p<0.01). These hearts depicted greater radiotracer activity in the inner than in the outer half wall sections of the transmural samples taken at regions of normal (3.4% vs. 1.1%), acute ischemic (3.3% vs. 0.2%), and necrotic myocardium (10.5% vs. 1.7%).
3.2 Uptake of 
Like 
-tetrofosmin, 
administered to beating hearts with acute peri-infarction ischemia either via the left atrium (group I) or the jugular vein (group II) induced a greater radiotracer uptake in the infarcted than in the acute ischemic region (Table 1). Median 
scintigraphic activity in the necrotic tissue was 8.6% of normal myocardium in group I and 15% in group II, whereas activity in acute ischemic myocardium was only 2.5% in group I and 3.3% in group II. Uptake of 
was homogeneous across the left ventricular wall and a significant fraction of this radiotracer was also detected in mitral valve leaflets and chordae tendineae (Table 1).
As shown in Table 3, intraventricular injection of 
in arrested hearts with blocked coronary circulation (group III) continued to elicit greater activity in the infarct scar than in acute ischemic myocardium (10% and 4.05% of the standard dose respectively, p<0.05). These hearts also showed greater 
activity in inner than in outer half wall sections. Scintigraphic views of myocardial samples confirmed the differential uptake of 
between necrotic and acute ischemic regions (Fig. 2).
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chloride in transmural left ventricular samples from pig hearts with a 1-month old anterior wall myocardial infarction submitted to 1 h of acute reocclusion of the left anterior descending coronary artery
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3.3 Histomorphologic examination
All pigs had a transmural myocardial infarct scar composed by fibroblasts, extracellular matrix, and few capillary vessels. Necrotic myocardial cells were heterogeneously distributed within the scar. Surviving myocardial cells were only observed in the subendocardium forming a band of about 0.25 mm width. The weight of the necrotic scar was 8.4±3.9 g (10.4±3.9% of total ventricular mass).
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4 Discussion |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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This study reveals that a 1-month old healed transmural myocardial infarction devoid of viable tissue can uptake significant fractions of
-tetrofosmin and 
. In addition, data show that radiotracer uptake in the infarct scar is significantly higher than that observed in contiguous acute ischemic myocardium.
The lack of radiotracer activity in the acute ischemic tissue is caused by the interruption of coronary perfusion and subsequent metabolic blockade, whereas the mechanism by which a healed myocardial infarction devoid of viable tissue extracts myocardial perfusion tracers is not known. Theoretically, accumulation of perfusion agents in the infarct region should only be possible via coronary collateral circulation or via diffusion from the intracavitary blood pool. Our data suggest that coronary collateral circulation was not a major source of radiotracer transport to the necrotic region because pigs with arrested hearts and blocked coronary circulation continued to depict greater uptake of 
-tetrofosmin and 
in the necrotic than in the acute ischemic region like pigs with beating hearts and unblocked coronary circulation. In agreement with the concept of a negligible role of coronary collateral circulation on radiotracer uptake in the infarct region other studies have reported that healthy and chronically infarcted pigs have a poor coronary collateral circulation [14–17].
Therefore, uptake of radiolabelled agents in the infarcted region is likely due to radiotracer extraction from the left ventricular cavity. Although there are no previous studies demonstrating accumulation of 
-tetrofosmin and 
in areas of healed myocardial infarction there are at least two findings supporting the hypothesis that radiotracers can accumulate in the fibrous infarcted tissue. One is based on the present observation that other fibrous tissues like the mitral valve leaflets and chordae tendineae also extract a high fraction of 
-tetrofosmin and 
. The second finding is that previous studies in sheep [9]and porcine hearts [18]revealed that areas of chronically infarcted myocardium have a low electrical tissue resistivity and this property implies, in turn, a high ionic diffusibility [19]. In addition, ionic compounds can also be attracted in the extracellular matrix of the connective tissue provided it is composed of water and electrically charged glycoproteins [10, 11]. However, the present study does not allow to ascertain whether radiotracers accumulate in the extracellular matrix or if, at the contrary, they are extracted by fibroblasts and endothelial cells inside the infarction. In fact, studies in murine hearts [12]have demonstrated that fibroblasts and endothelial cells of small capillaries uptake 
-sestamibi and 
. It seems unlikely that radiotracers were taken up by the thin layer of surviving subendocardial myocardial cells because a similar surviving cell band is observed one hour after coronary occlusion in the acute ischemic peri-infarction regions [14, 20]and, by contrast, these tissues showed a low 
-tetrofosmin and 
activity.
The outer wall sections of the infarcted region showed greater radiotracer activity in pigs injected during sinus rhythm than in pigs injected during cardiac arrest. These differences may indicate that the outer half wall regions of beating hearts receive a certain amount of radiotracer via coronary or extracoronary small epicardial collaterals. Alternatively, the lower activity in outer wall myocardial regions in arrested hearts may simply result from an incomplete radiotracer diffusion from the cavity.
4.1 Clinical implications
The observations made in this model may have a clinical counterpart because like pigs, humans with a permanent occlusion of a coronary artery develop transmural myocardial infarcts with a thin subendocardial layer of surviving cells [21]. This anatomical concordance is likely due to the fact that both mammalian hearts have a poorly developed coronary collateral circulation [16]. By contrast, dog hearts with abundant coronary collaterals develop nontransmural infarction after permanent coronary artery ligature [22–25]. The main clinical implication of our study is that although myocardial scintigraphic activity of 
-tetrofosmin and 
may identify areas of nonviable tissue as severe filling defects, a healed transmural infarction devoid of viable myocardial tissue may accumulate a significant fraction of 
-tetrofosmin and 
. Although 
-tetrofosmin counting in the infarct scar in our model is about 20% of that in normal myocardium, scintigraphic views of the whole heart performed in clinical practice may overcome this uptake because it is generally agreed that areas of radiotracer activity not exceeding 50% [6, 7]or 40% [8]of normal region in patients with previous infarction suggest infarcted or nonviable tissue. However, the concept that infarcted tissue may accumulate significant fractions of radiotracer is potentially relevant whenever new technological advances improve the sensitivity of scintigraphic systems to detect radiotracer activity.
Time for primary review 27 days.
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Acknowledgements |
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We appreciate the contribution of Dr. David Garc
éa-Dorado and Dr. Jagat Narula in reviewing the manuscript. This study was supported by grants from Hospital Vall d'Hebron (PRHG 33/96) and Fondo de Investigaciones Sanitarias de la Seguridad Social (95/1247 and 95/5115). |
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